Brimontim solopharm (Drops) Instructions for Use

Marketing Authorization Holder

Grotex, LLC (Russia)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Timolol (Rec.INN registered by WHO)

Brimonidine (Rec.INN registered by WHO)

Dosage Form

Brimontim solopharm

Eye drops 2 mg/ml+5 mg/ml

Dosage Form, Packaging, and Composition

Eye drops

10 ml – dropper bottles – cardboard packs – Prescription only
10 ml – dropper bottles (3 pcs.) – cardboard packs – Prescription only
10 ml – bottles – cardboard packs – Prescription only
10 ml – bottles (3 pcs.) – cardboard packs – Prescription only
3 ml – dropper bottles – cardboard packs – Prescription only
3 ml – dropper bottles (3 pcs.) – cardboard packs – Prescription only
3 ml – bottles – cardboard packs – Prescription only
3 ml – bottles (3 pcs.) – cardboard packs – Prescription only
5 ml – dropper bottles – cardboard packs – Prescription only
5 ml – dropper bottles (3 pcs.) – cardboard packs – Prescription only
5 ml – bottles – cardboard packs – Prescription only
5 ml – bottles (3 pcs.) – cardboard packs – Prescription only
7 ml – dropper bottles – cardboard packs – Prescription only
7 ml – dropper bottles (3 pcs.) – cardboard packs – Prescription only
7 ml – bottles – cardboard packs – Prescription only
7 ml – bottles (3 pcs.) – cardboard packs – Prescription only

Clinical-Pharmacological Group

Antiglaucoma drug

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; beta-adrenergic blockers, combinations with timolol

Pharmacological Action

A combined medicinal product for use in ophthalmology.

Brimonidine – an α-adrenergic receptor agonist. It has 1000 times greater selectivity for α₂-adrenergic receptors compared to α₁-adrenergic receptors. This selectivity is expressed in the absence of mydriasis and vasoconstriction of the microcirculatory bed vessels.

The hypotensive effect of brimonidine is provided by reducing the production of intraocular fluid and increasing its outflow through the uveoscleral pathway.

Timolol – a non-selective beta-adrenergic blocker, does not possess intrinsic sympathomimetic and membrane-stabilizing activity. Timolol reduces intraocular pressure (IOP) by decreasing the production of intraocular fluid.

The exact mechanism of action is not established; it may be associated with the inhibition of cAMP synthesis and is caused by endogenous stimulation of β-adrenergic receptors.

Both active substances reduce IOP through combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each component separately.

Pharmacokinetics

The mean C_max values in plasma for brimonidine and timolol after application of this combination were 0.0327 and 0.406 ng/ml, respectively.

Brimonidine

Brimonidine undergoes minimal metabolism in eye tissues. Plasma protein binding is about 29%. The T_1/2 of brimonidine after topical application is on average about 3 hours.

The main part of brimonidine (about 74% of the dose absorbed into the systemic circulation) is excreted by the kidneys as metabolites within 5 days; the unchanged substance was not found in urine.

In vitro studies on animal and human liver cells have shown that aldehyde oxidase and cytochrome P450 isoenzymes are significantly involved in the metabolism process.

Consequently, systemic elimination is determined primarily by the metabolism of brimonidine in the liver.

Timolol

80% of timolol with topical application enters the systemic circulation through absorption via the conjunctival vessels, nasal mucosa, and lacrimal tract. The C_max of timolol in the aqueous humor of the eye is reached in 1-2 hours. The T_1/2 of timolol in blood plasma is about 7 hours.

Timolol binds slightly to plasma proteins. Timolol is partially metabolized in the liver; the active substance and its metabolites are excreted by the kidneys.

Indications

Open-angle glaucoma; ocular hypertension (with insufficient effectiveness of local therapy with beta-blockers).

ICD codes

Dosage Regimen

Instill one drop into the affected eye(s) twice daily, approximately every 12 hours.

Do not exceed the recommended dosage.

If using other topical ophthalmic products, administer them at least 5 minutes apart.

To prevent contamination of the dropper tip and solution, avoid contact with the eyelids, surrounding areas, or any other surfaces.

Close the bottle tightly immediately after use.

If a dose is missed, apply it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and continue with the regular schedule.

Regular intraocular pressure monitoring is required to assess therapeutic response.

In patients with severely compromised corneal epithelium, exercise caution, as the effects of the active ingredients may be potentiated.

Adverse Reactions

Eye disorders: very common – conjunctival hyperemia, burning sensation; common – acute burning or stinging pain, allergic conjunctivitis, corneal erosion, superficial keratitis, eyelid skin itching, conjunctival folliculosis, visual impairment, blepharitis, epiphora, eye dryness, eye discharge, pain, eye irritation, foreign body sensation; uncommon – decreased visual acuity, conjunctival edema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, vitreous floaters, asthenopia, photophobia, hypertrophy of the eye’s papillary muscles, eyelid pain, conjunctival pallor, corneal edema, corneal infiltrates, vitreous detachment; possible – iridocyclitis, miosis, decreased corneal sensitivity, diplopia, ptosis, choroidal rupture (after filtering surgery), refraction changes (due to withdrawal of miotic therapy in some cases).

Psychiatric disorders common – depression; possible – insomnia, nightmares, decreased libido.

Nervous system disorders common – drowsiness, headache; uncommon – dizziness, syncope; possible – memory loss, worsening of myasthenia symptoms, paresthesia, cerebral ischemia.

Cardiovascular system disorders common – increased BP; uncommon – congestive heart failure, palpitations; frequency unknown – arrhythmia, bradycardia, tachycardia, decreased BP; possible complete heart block, cardiac arrest, cerebrovascular accident, intermittent claudication, Raynaud’s syndrome, cold extremities.

Respiratory system disorders uncommon – rhinitis, nasal dryness; possible – upper respiratory tract inflammatory diseases, dyspnea; possible – bronchospasm (mainly in patients with a history of bronchospastic diseases), dyspnea, cough, respiratory failure.

Gastrointestinal system disorders common – dry mouth; uncommon – taste perversion; possible dyspepsia.

Ear and labyrinth disorders possible – tinnitus.

Skin and subcutaneous tissue disorders: common – eyelid edema, eyelid skin itching, eyelid skin redness; uncommon – allergic contact dermatitis.

General disorders and administration site conditions: common – asthenic conditions; possible – peripheral edema, Peyronie’s disease, chest pain, systemic lupus erythematosus.

Investigations common – increased liver enzyme activity.

Contraindications

Hypersensitivity to the components of the combination; increased respiratory reactivity, including bronchial asthma and episodes of bronchospasm, including in history, severe COPD; sinus bradycardia, second- or third-degree AV block without an implanted artificial pacemaker, heart failure, cardiogenic shock; concomitant therapy with MAO inhibitors, tricyclic and tetracyclic antidepressants (including mianserin); children and adolescents under 18 years of age; breastfeeding period.

With caution

Renal/hepatic insufficiency (use of the drug is insufficiently studied in this group of patients); depression, cerebral or coronary insufficiency, Raynaud’s syndrome, orthostatic hypotension, obliterative thromboangiitis; severe unstable cardiovascular diseases; diabetes mellitus, episodes of hypoglycemia (in the absence of therapy); pheochromocytoma (without prior treatment); metabolic acidosis; simultaneous use of radiocontrast agents; intravenous administration of lidocaine, calcium channel blockers (verapamil, diltiazem) due to the risk of AV conduction depression, bradycardia, heart failure and decreased BP; simultaneous administration or change in the dose of drugs from the groups of adrenergic agonists (isoprenaline) and adrenergic blockers (prazosin), as well as other agents affecting adrenergic transmission – due to their possible interaction with the active components of the combination or change in their therapeutic potential.

Use in Pregnancy and Lactation

There are no data on the use of brimonidine in pregnant women. Animal studies have demonstrated reproductive toxicity at high doses of brimonidine that had toxic effects on the mother. The degree of risk to humans is not established.

Animal studies have established reproductive toxicity of timolol when used in doses significantly exceeding those recommended for clinical use. Epidemiological studies have not revealed congenital fetal malformations, but the risk of intrauterine growth retardation is known with oral intake of drugs from the beta-blocker group.

In addition, symptoms characteristic of the beta-blocker group (bradycardia, decreased BP, respiratory distress and hypoglycemia) were observed in newborns in cases where beta-blockers were used by the mother until delivery.

Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Use with caution in renal insufficiency.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Prescribed for adults, including elderly patients.

Special Precautions

Systemic absorption of the combination components is possible.

If allergic reactions occur, treatment should be discontinued.

In patients with severe renal impairment on hemodialysis, treatment with timolol is accompanied by a pronounced decrease in BP.

Against the background of taking a drug from the beta-blocker group, patients with agonistic manifestations and severe anaphylactic reactions to various allergens in history may have reduced or no effectiveness from the administration of epinephrine in usually used doses.

Beta-blockers can also mask the symptoms of hyperthyroidism and worsen the course of Prinzmetal’s angina, vascular diseases, both peripheral and central, as well as arterial hypotension.

Signs indicating acute hypoglycemia, in particular, tachycardia, palpitations and sweating, may be masked during therapy with beta-blockers.

If it is necessary to discontinue therapy with this combination, as well as in the treatment of cardiovascular diseases with systemic beta-blockers, therapy is withdrawn gradually to avoid the development of cardiac arrhythmias, myocardial infarction and/or sudden death, the risk of which increases with abrupt withdrawal of drugs of this group.

Effect on the ability to drive vehicles and machinery

The Brimonidine + Timolol combination has a slight effect on the ability to drive vehicles and machinery. During treatment, transient visual impairment (blurring), episodes of weakness and drowsiness may develop, which may adversely affect if the patient’s work is associated with potentially hazardous activities.

If these symptoms occur, one should refrain from potentially hazardous activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

The possibility of enhancing the effect of drugs that depress the CNS (alcohol, barbiturates, opiate derivatives, sedatives, general anesthetics) with simultaneous use with this combination should be considered.

Timolol may exacerbate compensatory tachycardia and increase the risk of a pronounced decrease in BP when used with general anesthetics. The anesthesiologist should be warned about the use of this drug before the upcoming surgery.

With simultaneous use of timolol and epinephrine, mydriasis may develop.

Beta-blockers may enhance the hypoglycemic effect of hypoglycemic drugs. They may also mask hypoglycemia.

The hypertensive reaction to the sudden withdrawal of clonidine may be enhanced against the background of the use of a beta-blocker.

Enhancement of the hypotensive effect (e.g., decreased heart rate) when using timolol together with quinidine is possible, since quinidine slows down the metabolism of timolol via the CYP2D6 isoenzyme.

Cimetidine, hydralazine, ethanol may increase the plasma concentration of timolol.

Medicinal products that affect the metabolism and uptake of circulating catecholamines, such as chlorpromazine, methylphenidate, reserpine, should be used with caution. Concomitant use of MAO inhibitors is contraindicated. In patients who have received MAO inhibitors, the use of this combination is possible no earlier than 14 days after discontinuation of the MAO inhibitor.

Potentiation of effects has been reported with the combined use of eye drops containing Timolol and orally taken calcium channel blockers, guanethidine or beta-blockers, antiarrhythmic drugs, cardiac glycosides or parasympathomimetics, manifested by a pronounced decrease in BP and/or severe bradycardia.

After the use of brimonidine, a decrease in BP has been reported in very rare cases (<1/10000). Therefore, this combination should be used with caution together with drugs that have a systemic hypotensive effect.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.